Loses of noradrenergic and cholinergic markers from a number of brain region, particularly the cerebral cortex have been recognized in SDAT. These losses are accompanied by lesions of the locus coeruleus (LC) and substantia innominata (SI), the respective in trinsic source of the neurotransmitters. A functional interaction between these systems seems probable from indirect experimental evidence. However it is unknown whether the function of the SI is regulated by noradrenergic projections and whether these projections also influence target cells of the SI in the cerebral cortex. These issues will be addressed by the present proposal. Microphysiological methods would be used to measure changes in extracellular activity of single neurons in response to synaptic activation and to the microelectrophoretic administration of drugs. Specifically the following questions would be probed: (1) Does the SI receive input from the LC, are these arranged topographically, and can their activation be mimicked by the administration of norepinephrine; (2) What is the character of synaptic activity evoked in the cortex by SI stimulation and are the target cells cholinoceptive; (3) Does the LC supply converging input to the same cortical cells; if so, what is the nature of the synaptic interaction between SI and LC inputs; (4) Do NE or ACh, administered at various doses affect the synaptic input of cortical target cells; (5) How do cortical cells respond to various dose combinations of norepinephrine and acetylcholine; (6) If an interaction exists, what types of pharmacological receptors are involvd, i.e., Alpha, Beta-adrenoceptors. This study would provide fundamental information concerning the function and projections of major noradrenergic and cholinergic pathways. It would give further information about the potential significance of noradrenergic/cholinergic interactions in brain and describe the pharmacology of these interactions. These studies are important for understanding the etiology of SDAT and for providing rationale for future therapeutic thrust in this disease.